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A compound library screen identified 2\u2010thiophenesulfonamide compounds that specifically inhibit <jats:italic>Vibrio\u00a0campbellii<\/jats:italic> LuxR but do not affect cell growth. We synthesized a panel of 50 thiophenesulfonamide compounds to examine the structure\u2013activity relationship effects on <jats:italic>Vibrio<\/jats:italic> quorum sensing. The most potent molecule identified, PTSP (3\u2010<jats:styled-content>p<\/jats:styled-content>henyl\u20101\u2010(<jats:styled-content>t<\/jats:styled-content>hiophen\u20102\u2010yl<jats:styled-content>s<\/jats:styled-content>ulfonyl)\u20101<jats:italic>H<\/jats:italic>\u2010<jats:styled-content>p<\/jats:styled-content>yrazole), inhibits quorum sensing in multiple strains of <jats:italic>V.\u00a0vulnificus, V.\u00a0parahaemolyticus<\/jats:italic>, and <jats:italic>V.\u00a0campbellii<\/jats:italic> at nanomolar concentrations. However, thiophenesulfonamide inhibition efficacy varies significantly among <jats:italic>Vibrio<\/jats:italic> species: PTSP is most inhibitory against <jats:italic>V.\u00a0vulnificus<\/jats:italic> SmcR, but <jats:italic>V.\u00a0cholerae<\/jats:italic> HapR is completely resistant to all thiophenesulfonamides tested. Reverse genetics experiments show that PTSP efficacy is dictated by amino acid sequence in the putative ligand\u2010binding pocket: F75Y and C170F SmcR substitutions are each sufficient to eliminate PTSP inhibition. Further, in silico modeling distinguished the most potent thiophenesulfonamides from less\u2010effective derivatives. Our results revealed the previously unknown differences in LuxR\/HapR proteins that control quorum sensing in <jats:italic>Vibrio<\/jats:italic> species and underscore the potential for developing thiophenesulfonamides as specific quorum sensing\u2010directed treatments for <jats:italic>Vibrio<\/jats:italic> infections.<\/jats:p>","DOI":"10.1111\/mmi.14804","type":"journal-article","created":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T09:27:02Z","timestamp":1630488422000},"page":"1173-1188","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Amino acid divergence in the ligand\u2010binding pocket of <i>Vibrio<\/i> LuxR\/HapR proteins determines the efficacy of thiophenesulfonamide inhibitors"],"prefix":"10.1111","volume":"116","author":[{"given":"Jane D.","family":"Newman","sequence":"first","affiliation":[{"name":"Department of Biology Indiana University Bloomington Indiana 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